Limited Blood-brain Barrier Penetration Research Articles

Abstract 6472: Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system

Abstract Background: Central nervous system (CNS) metastasis from breast cancer can be challenging to treat due to the limited blood brain barrier penetration of many systemic therapies. PARP inhibitors (PARPi) block single-strand DNA break repairs and have activity in cancers with homologous recombination repair deficiency; they are FDA approved for patients with metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. While preclinical studies suggest that PARPi have CNS penetration, clinical data is limited. The goal of our study is to describe the clinical benefit of PARPi in patients with breast cancer CNS metastasis. Methods: This retrospective case series was conducted at three academic cancer centers (Johns Hopkins, Dana-Farber, and Duke) and included patients with the following criteria: (1) age≥18 years with a breast cancer diagnosis (any subtype); (2) diagnosis of parenchymal brain metastasis or leptomeningeal disease (LMD); and (3) received PARPi (olaparib, talazoparib) for CNS metastasis. Clinical and pathologic information were analyzed with descriptive statistics (median, range) and Kruskal-Wallis rank sum tests. Survival analysis was performed using Kaplan-Meier curves with log-rank p-values. Results: Although this analysis includes one center’s experience, we will present a combined dataset (N = 45) at the main conference. 11 patients were identified at Johns Hopkins. 4 (36.4%) were Black and 6 (54.5%) were White; 6 (54.5%) had ER+HER2- disease and 5 (45.5%) had TNBC at time of brain metastasis; 5 (45.5%) had BRCA1 mutations, 5 (45.5%) had a BRCA2 mutations, and 1 patient (9%) had a BARD1 mutation; 7 (63.6%) had brain metastasis and 4 (36.4%) had LMD. Median lines of therapy prior to PARPi was 6 [1 - 11]; 8 patients (72.7%) had previous CNS radiation (5 SRS and 3 WBRT) and 3 (27.3%) had previous CNS surgery. On average, patients remained on PARPi for 5 months [0.5 - 66], and overall survival (OS) time from PARPi to death was 16 months [2 - 66]. Time on PARPi was 5 months [2 - 66] for patients with brain metastasis and 3 months [0.5 - 10] for those with LMD (p=0.22). Duration of PARPi and OS did not differ significantly between ER+HER2- and TNBC (p=0.74 and 0.69, respectively), BRCA 1 and 2 (p=0.78 and 0.72, respectively), or brain and LMD metastasis (p=0.22 and 0.91, respectively). Black patients had significantly shorter PARPi duration and survival than White patients (PARPi 2 vs. 8 months, p=0.028 and OS 4 vs 18 months, p=0.028). Prior CNS radiation was significantly associated with longer PARPi duration and survival (PARPi 5 vs 1 month, p=0.02 and OS 17 vs. 3 months, p=0.032). Prior CNS surgery was significantly associated with longer PARPi duration, but not overall survival (PARPi 18 vs 3 months, p=0.05 and OS 28 vs. 7 months, p=0.14). Conclusions: PARPi are associated with significant clinical benefit in patients with breast cancer CNS metastasis. Larger data series will help confirm these observations. Citation Format: Seoho Lee, Rani Bansal, Melissa E. Hughes, Amanda E. Van Swearingen, Heather N. Moore, David O. Kamson, Solmaz Sahebjam, Greg Kirkner, Anna Gorfinkel, Sarah Sammons, Nancy U. Lin, Carey Anders, Cesar A. Santa-Maria. Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6472.

Cost-effectiveness of rezvilutamide versus bicalutamide and androgen-deprivation therapy in patients with highvolume, metastatic, hormone-sensitive prostate cancer.

Background: Rezvilutamide, a novel androgen-receptor inhibitor with limited blood-brain barrier penetration, exhibits significant antitumour activity against highvolume, metastatic, hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to compare the cost-effectiveness of rezvilutamide and bicalutamide as first-line treatments for untreated prostate cancer among Chinese patients, in order to evaluate the efficacy of rezvilutamide. Methods: In this study, we utilized partition survival model to assess the cost-effectiveness of rezvilutamide and bicalutamide treatments for highvolume mHSPC. The model was developed using TreeAge Pro 2022 software and relied on clinical data obtained from the CHART trial. Transition probabilities were estimated from the reported survival probabilities in trials using parametric survival modeling. From the perspective of the Chinese healthcare system, we calculated quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and lifetime cost. A lifetime horizon and an annual discount rate of 5% were employed. To address modeling uncertainties, we conducted one-way sensitivity analysis and probabilistic sensitivity analysis. Results: The cost of rezvilutamide versus bicalutamide were $62700 and $13200. Rezvilutamide had an ICER of $41900 per additional QALYs gained compared with bicalutamide. Research indicated that rezvilutamide achieved at least an 28.20% probability of cost-effectiveness at the threshold of $38223.34/QALY. One-way sensitivity analysis revealed that the results were sensitive to utility of PD. Scenario analysis showed that rezvilutamide was cost-effectiveness if its price was reduced by more than 10%. Conclusion: Based on the analysis at the current price, rezvilutamide was found to be less cost-effective for patients with highvolume mHSPC compared to bicalutamide in China.

Efficacy of convection enhanced delivery of MTX110 (soluble panobinostat) in preclinical Diffuse Intrinsic Pontine Glioma models using metabolic hyperpolarized 13C imaging

BackgroundDiffuse intrinsic pontine glioma (DIPG) usually occurs in children and has poor outcomes despite treatment. Large drug screens have identified the pan-histone deacetylate inhibitor panobinostat as a promising agent, however clinical response might be hampered by limited blood brain barrier penetration. Hyperpolarized 13C magnetic resonance (MR) metabolic imaging has successfully been applied to non-invasively assess metabolic activity of cancer therapies. Here, we use in vitro and in vivo DIPG models to validate the therapeutic efficacy of MTX110, an aqueous form of panobinostat delivered by convection enhanced delivery (CED) and apply metabolic imaging. MethodsMTX110 inhibitory effect was assessed in 11 DIPG cell lines. Caspase 3/7 levels were measured to assess mode of cell death. FACS analysis was utilized to determine impact on cell cycle. Hyperpolarized 13C imaging determined changes in pyruvate and lactate levels after treatment. In vivo activity of CED of MTX110 was assessed in a patient-derived xenograft rat model and tissue half-life of MTX110 was determined using mass spectrometry. ResultsMTX110 showed similar IC50 to panobinostat ranging from 5.34 nM and 47.96 nM. Anti-proliferative effects of MTX110 are mediated by G1 cell cycle arrest and subsequent apoptosis. Drug treatment led to reduced pyruvate to lactate conversion. CED of MTX110 significantly prolonged survival of tumor-bearing rats (p = 0.0372) with no signs of systemic toxicity. Tissue half-life after single CED of MTX110 is 2 h. ConclusionsOur results demonstrate that CED of MTX110, has potent antitumor activity with limited systemic toxicity and that hyperpolarized 13C imaging is able to assess metabolic impact.

Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development.

Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14–15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood–brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.

A novel GABAA receptor ligand MIDD0301 with limited blood-brain barrier penetration relaxes airway smooth muscle ex vivo and in vivo.

Airway smooth muscle (ASM) cells express GABA A receptors (GABAARs), and previous reports have demonstrated that GABAAR activators relax ASM. However, given the activity of GABAARs in central nervous system inhibitory neurotransmission, concern exists that these activators may lead to undesirable sedation. MIDD0301 is a novel imidazobenzodiazepine and positive allosteric modulator of the GABAAR with limited brain distribution, thus eliminating the potential for sedation. Here, we demonstrate that MIDD0301 relaxes histamine-contracted guinea pig ( P < 0.05, n = 6-9) and human ( P < 0.05, n = 6-10) tracheal smooth muscle ex vivo in organ bath experiments, dilates mouse peripheral airways ex vivo in precision-cut lung-slice experiments ( P < 0.001, n = 16 airways from three mice), and alleviates bronchoconstriction in vivo in mice, as assessed by the forced-oscillation technique ( P < 0.05, n = 6 mice). Only trace concentrations of the compound were detected in the brains of mice after inhalation of nebulized 5 mM MIDD0301. Given its favorable pharmacokinetic properties and demonstrated ability to relax ASM in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases, such as asthma.

MTE26.02 EGFR Targeted Therapies: Lessons Learned

MTE26.02 EGFR Targeted Therapies: Lessons Learned

Treatment of brain metastases in the modern genomic era.

Development of brain metastasis (BM) portends a dismal prognosis for patients with cancer. Melanomas and carcinomas of the lung, breast, and kidney are the most common malignancies to metastasize to the brain. Recent advances in molecular genetics have enabled the identification of actionable, clinically relevant genetic alterations within primary tumors and their corresponding metastases. Adoption of genotype-guided treatment strategies for the management of systemic malignancy has resulted in dramatic and durable responses. Unfortunately, despite these therapeutic advances, central nervous system (CNS) relapses are not uncommon. Although these relapses have historically been attributed to limited blood brain barrier penetration of anti-neoplastic agents, recent work has demonstrated genetic heterogeneity such that metastatic sites, including BM, harbor relevant genetic alterations that are not present in primary tumor biopsies. This improved insight into molecular mechanisms underlying site specific recurrences can inform strategies for targeting these oncogenic drivers. Thus, development of rational, genomically guided CNS-penetrant therapies is crucial for ongoing therapeutic success.

Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery

Central nervous system (CNS) drug delivery is often hampered due to the insidious nature of the blood-brain barrier (BBB). Nose-to-brain delivery via olfactory pathways have become a target of attention for drug delivery due to bypassing of the BBB. The antioxidant properties of phytochemicals make them promising as CNS active agents but possess poor water solubility and limited BBB penetration. The primary aim of this study was the development of mesoporous silica nanoparticles (MSNs) loaded with the poorly water-soluble phytochemicals curcumin and chrysin which could be utilised for nose-to-brain delivery. We formulated spherical MSNP using a templating approach resulting in ∼220nm particles with a high surface porosity. Curcumin and chrysin were successfully loaded into MSNP and confirmed through Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and HPLC approaches with a loading of 11–14% for curcumin and chrysin. Release was pH dependant with curcumin demonstrating increased chemical stability at a lower pH (5.5) with a release of 53.2%±2.2% over 24h and 9.4±0.6% for chrysin. MSNP were demonstrated to be non-toxic to olfactory neuroblastoma cells OBGF400, with chrysin (100μM) demonstrating a decrease in cell viability to 58.2±8.5% and curcumin an IC50 of 33±0.18μM. Furthermore confocal microscopy demonstrated nanoparticles of <500nm were able to accumulate within cells with FITC-loaded MSNP showing membrane localised and cytoplasmic accumulation following a 2h incubation. MSNP are useful carriers for poorly soluble phytochemicals and provide a novel vehicle to target and deliver drugs into the CNS and bypass the BBB through olfactory drug delivery.

AZD3759, an EGFR inhibitor with blood brain barrier (BBB) penetration for the treatment of non-small cell lung cancer (NSCLC) with brain metastasis (BM): Preclinical evidence and clinical cases.

8016 Background: Increasing numbers of EGFRm+ NSCLC patients with BM have been reported, while effective treatment is lacking due to limited BBB penetration of currently available EGFR TKIs. Here w...

The Effect of ABCG2 and ABCC4 on the Pharmacokinetics of Methotrexate in the Brain

Methotrexate (MTX) is the cornerstone of chemotherapy for primary central nervous system lymphoma, yet how the blood-brain barrier (BBB) efflux transporters ABCG2 and ABCC4 influence the required high-dose therapy is unknown. To evaluate their role, we used four mouse strains, C57BL/6 (wild-type; WT), Abcg2(-/-), Abcc4(-/-), and Abcg2(-/-);Abcc4(-/-) (double knockout; DKO) to conduct brain microdialysis studies after single intravenous MTX doses of 50 mg/kg. When the area under the concentration-time curve for plasma (AUC(plasma)) was used to assess systemic exposure to MTX, the rank order was Abcc4(-/-) < WT < Abcg2(-/-) < Abcg2(-/-)Abcc4(-/-). Only the DKO exposure was significantly higher than that of the WT group (P < 0.01), a reflection of the role of Abcg2 in biliary excretion and Abcc4 in renal excretion. MTX brain interstitial fluid concentrations obtained by microdialysis were used to calculate the area under the concentration-time curve for the brain (AUC(brain)), which found the rank order of exposure to be WT < Abcc4(-/-) < Abcg2(-/-) < Abcg2(-/-)Abcc4(-/-) with the largest difference being 4-fold: 286.13 ± 130 μg*min/ml (DKO) versus 66.85 ± 26 (WT). Because the transporters affected the systemic disposition of MTX, particularly in the DKO group, the ratio of the AUC(brain)/AUC(plasma) or the brain/plasma partition coefficient Kp was calculated, revealing that the DKO strain had a significantly higher value (0.23 ± 0.09) than the WT strain (0.11 ± 0.05). Both Abcg2 and Abcc4 limited BBB penetration of MTX; however, only when both drug efflux pumps were negated did the brain accumulation of MTX significantly increase. These findings indicate a contributory role of both ABCG2 and ABCC4 to limiting MTX distribution in patients.

Pharmacological characterization of AM1710, a putative cannabinoid CB 2 agonist from the cannabilactone class: Antinociception without central nervous system side-effects

Cannabinoid CB 2 agonists produce antinociception without central nervous system (CNS) side-effects. This study was designed to characterize the pharmacological and antinociceptive profile of AM1710, a CB 2 agonist from the cannabilactone class of cannabinoids. AM1710 did not exhibit off-target activity at 63 sites evaluated. AM1710 also exhibited limited blood brain barrier penetration. AM1710 was evaluated in tests of antinociception and CNS activity. CNS side-effects were evaluated in a modified tetrad (tail flick, rectal temperature, locomotor activity and rota-rod). Pharmacological specificity was established using CB 1 (SR141716) and CB 2 (SR144528) antagonists. AM1710 (0.1–10 mg/kg i.p.) produced antinociception to thermal but not mechanical stimulation of the hindpaw. AM1710 (5 mg/kg i.p.) produced a longer duration of antinociceptive action than the aminoalkylindole CB 2 agonist ( R,S)-AM1241 (1 mg/kg i.p.) at maximally antinociceptive doses. Antinociception produced by the low (0.1 mg/kg i.p.) dose of AM1710 was blocked selectively by the CB 2 antagonist SR144528 (6 mg/kg i.p.), whereas antinociception produced by the high dose of AM1710 (5 mg/kg i.p.) was blocked by either SR144528 (6 mg/kg i.p.) or SR141716 (6 mg/kg i.p.). AM1710 did not produce hypoactivity, hypothermia, tail flick antinociception, or motor ataxia when evaluated in the tetrad at any dose. In conclusion, AM1710, a CB 2-preferring cannabilactone, produced antinociception in the absence of CNS side-effects. Thus, any CB 1-mediated antinociceptive effects of this compound may be attributable to peripheral CB 1 activity. The observed pattern of pharmacological specificity produced by AM1710 is consistent with limited blood brain barrier penetration of this compound and absence of CNS side-effects.

Aldosterone in the brain

Pharmacological and physiological phenomena suggest that cells somewhere inside the central nervous system are responsive to aldosterone. Here, we present the fundamental physiological limitations for aldosterone action in the brain, including its limited blood-brain barrier penetration and its substantial competition from glucocorticoids. Recently, a small group of neurons with unusual sensitivity to circulating aldosterone were identified in the nucleus of the solitary tract. We review the discovery and characterization of these neurons, which express the enzyme 11beta-hydroxysteroid dehydrogenase type 2, and consider alternative proposals regarding sites and mechanisms for mineralocorticoid action within the brain.

Catecholamine Secretory Vesicle Stimulus-Transcription Coupling in Vivo: DEMONSTRATION BY A NOVEL TRANSGENIC PROMOTER/PHOTOPROTEIN REPORTER AND INHIBITION OF SECRETION AND TRANSCRIPTION BY THE CHROMOGRANIN A FRAGMENT CATESTATIN

Stimulation of chromaffin cell secretion in vitro triggers not only secretion but also resynthesis of just released catecholamines and chromogranin A, the precursor of the catecholamine release-inhibitory, nicotinic cholinergic antagonist peptide catestatin. Does stimulus-transcription coupling occur in vivo? And does catestatin antagonize secretion and transcription in vivo? To answer these questions, we employed a novel mouse strain harboring a chromogranin A promoter/firefly luciferase reporter transgene. Tissue-specific expression of the reporter was established by both luminescence and reverse transcription-PCR. Secretion and transcription in vivo were triggered by either direct nicotinic stimulation or vesicular transmitter depletion. Nicotinic blockade in vivo was attempted with either the classical antagonist chlorisondamine or the novel antagonist catestatin. Luciferase reporter expression was exquisitely sensitive over a large dynamic range, was specific for the transgenic animals, and paralleled typical neuroendocrine distribution of endogenous chromogranin A. Adrenal ontogeny revealed a rise of embryonic transgene expression until embryonal day 18, with an abrupt postnatal decline. Direct nicotinic stimulation of chromaffin cells caused catecholamine release and transgene transcription, each of which was nearly completely blocked by chlorisondamine. Similar adrenal results were obtained during vesicular catecholamine depletion. Both secretion and transcription were substantially blocked in the adrenal gland by catestatin. In brain and sympathetic nerve, stimulation of transcription was more modest, and reserpine responses were only incompletely blocked by chlorisondamine or catestatin, perhaps because of limited blood-brain barrier penetration by these cationic antagonists. Thus, nicotinic cholinergic stimulus-transcription coupling occurs in vivo and can be provoked either directly or indirectly (by vesicular transmitter depletion). Such coupling triggers the biosynthesis of chromogranin A, the precursor of catestatin. Catestatin itself blocks stimulation of both secretion and transcription in vivo. Thus, chromogranin A and its catestatin fragment may lie at the nexus of nicotinic cholinergic signaling in vivo.

The CRF 1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist

Corticotropin releasing factor (CRF) is the key coordinator of the neuroendocrine and behavioral responses to stress. In the central nervous system, CRF excites select neuronal populations, and infusion of CRF into the cerebral ventricles of infant rats produces severe age-dependent limbic seizures. These seizures, like other CRF effects, result from activation of specific receptors. Both of the characterized members of the CRF receptor family (CRF 1 and CRF 2), are found in the amygdala, site of origin of CRF-induced seizures, and may therefore mediate these seizures. To determine which receptor is responsible for the excitatory effects of CRF on limbic neurons, a selective, non-peptide CRF 1 antagonist was tested for its ability to abolish the seizures, in comparison to non-selective inhibitory analogues of CRF. Pretreatment with the selective CRF 1 blocker (NBI 27914) increased the latency and decreased the duration of CRF-induced seizures in a dose-dependent manner. The higher doses of NBI 27914 blocked the behavioral seizures and prevented epileptic discharges in concurrent electroencephalograms recorded from the amygdala. The selective CRF 1 blocker was poorly effective when given systemically, consistent with limited blood-brain barrier penetration. Urocortin, a novel peptide activating both types of CRF receptors in vitro, but with preferential affinity for CRF 2 receptors in vivo, produced seizures with a lower potency than CRF. These limbic seizures, indistinguishable from those induced by CRF, were abolished by pretreatment with NBI 27914, consistent with their dependence on CRF 1 activation. In summary, CRF induces limbic seizures in the immature rat, which are abolished by selective blocking of the CRF 1 receptor. CRF 1-messenger RNA levels are maximal in sites of seizure origin and propagation during the age when CRF is most potent as a convulsant. Taken together, these facts strongly support the role of the developmentally regulated CRF 1 receptor in mediating the convulsant effects of CRF in the developing brain.